Abstract: Ions and membrane phospholipids can undergo dynamic transbilayer movement. While membrane ion transport mediated by ion channels and pumps is well appreciated in health and disease, the molecular mechanism, cellular function, physiological and pathological importance of membrane phospholipid transport are still poorly understood. Recently, I and others discovered that the newly discovered TMEM16 membrane protein family includes both ion channels and lipid scramblases. These findings open up unique opportunities to tackle the poorly understood lipid transport phenomenon. I propose herein a novel phospholipid-mediated cell signaling paradigm that is distinct from the canonical lipid signaling mechanism. In this paradigm, phospholipids, instead of being enzymatically metabolized, undergo dynamic transbilayer redistribution. This rapid transbilayer lipid transport mediated by TMEM16F lipid scramblase can spatiotemporally change the local/global lipid composition, and subsequently alter the membrane association of various signaling proteins and their downstream signaling cascades. I will test this new signaling paradigm by genetically and pharmacologically manipulating the TMEM16F- mediated phosphatidylserine (PS) exposure. Particularly, I will examine the effects of TMEM16F- mediated phospholipid transport on the PS binding proteins and their downstream signaling pathways in vitro. I will examine the physiological roles of TMEM16F in the excitable neurons and nonexcitable glial cells, two major cell types in the brain, to investigate the in vivo functions of the lipid scramblase. I will also develop pharmacological reagents to manipulate TMEM16F function. My overall goal is to understand the molecular, cellular and physiological mechanisms of transbilayer lipid phenomenon and its impacts on human health and disease.